Blood flow reductions in the heart can result in dysfunction of this organ and cell death if the flow reduction is severe enough. Restoration of coronary blood flow early during a heart attack is becoming a clinical reality with the advent and improvements in thrombolytic, mechanical, and surgical interventions. While early restoration of blood flow, for example, by thrombolysis or following transient ischemia, can prevent or mitigate the degree of cell death (infarction) occurring, reperfusion can still result in some degree of cardiac dysfunction or cell death (also referred to as stunned myocardia). Thus, it would be of great clinical value to find a means to preserve reperfusion function of the heart.
Thromboxane A.sub.2 (TXA) which is released from the heart during reperfusion is thought to have physiological effects that may adversely influence myocardial performance, namely, TXA contributes to post ischemic contractile dysfunction, Hoeft, A., et al, "Preservation of myocardium in transient ischemia by the thromboxane synthetase inhibitor UK-38,485." Res. Exp. Med. 1986; 186:35-46, and Schror, K., et al, "Treatment of acute myocardial ischemia with a selective antagonist of thromboxane receptors. (BM 13,177)" Br. J. Pharmacol. 1986; 87:631-7.
Hoeft et al, supra, and Schror et al, supra, demonstrate the ability of certain TXA inhibitors and antagonists to reduce the severity of ischemia in some experimental models, though the physiological mechanisms of action of these compounds on post-ischemic recovery of function are still unknown. For instance, it is thought that TXA is released during ischemia as well as during reperfusion and thus TXA antagonists may be working during coronary occlusion, Schmitz, J. M., et al, "Vascular prostaglandin and thromboxane production in a canine model of myocardial ischemia." Circ. Rec. 1985; 67:223-31, Michael, L. H., et al, "Myocardial ischemia: platelet and thromboxane concentrations in cardiac lymph and the effects of ibuprofen and prostacyclin." Circ. Res. 1986; 59:49-55.
Available therapies for reperfusion of occluded blood vessels include intravenous or intracoronary administration of a plasminogen activator, i.e., thrombolytic therapy. Examples of plasminogen activators used in thrombolytic therapy are streptokinase, urokinase and tissue plasminogen activator (t-PA).
Thrombolytic therapy at best, even using the preferred t-PA, can only re-establish antegrade flow in an infarcted artery. Thrombolytic therapy will not reverse the factors responsible for initiation of the thrombus such as advanced atherosclerotic plaques, intimal rupture, enhanced platelet adherence and aggregability or coronary spasm. Patients with a residual stenosis of greater than 80%, after successful recanalization with t-PA, are at an extremely high risk of rethrombosis even in the presence of high dose heparin. In addition to persistent reocclusion, systemic bleeding can be associated with administration of high doses of t-PA.
Thromboxane synthetase inhibitors have been demonstrated to be efficacious in inhibiting platelet aggregation in various animal models of platelet activation. See Schumacher et al, J. Pharmacol. Exp. Ther. 227:790 (1983). Aiken et al, J. Pharmacol. Exp. Ther. 219:299 (1981) demonstrated that endogenous prostacyclin contributed to the efficacy of thromboxane synthetase inhibition via diversion or "steal" of platelet-derived endoperoxides to form prostacyclin.
Schumacher et al, J. Cardiol. Pharmacol. 7:739 (1985), report that prostacyclin augments streptokinase-induced coronary thrombolysis in the dog.
Mickelson, J. K. et al, Am. Heart J., June, 1987, p. 1345-1352, reports that CGS 13080, a thromboxane synthetase inhibitor, inhibits reocclusion following streptokinase-induced reperfusion after thrombotic occlusion of the circumflex coronary artery in a dog model.
European patent application No. 0265129Al published Apr. 27, 1988, discloses a thrombolytic therapy which is a combination of a plasminogen activator and an agent which lowers the effective plasminogen activator dose requirement and which results in a lower incidence of reocclusion, which agent is an inhibitor of thromboxane activity, that is inhibits thromboxane-induced platelet aggregation. Such agents which inhibit thromboxane-induced platelet aggregation include thromboxane synthetase inhibitors and antagonists of platelet thromboxane receptors; thromboxane receptor antagonists disclosed include: EP045 and EP092 [Armstrong et al, Br. J. Pharmacol. 84:595 (1985)];
4-[2-(benzenesulfonamido)ethyl]phenoxyacetic acid (BM 13,177) [Patscheke et al, Thromb. Res. 33:277 (1984); U.S. Pat. No. 4,433,477];
4-[2-(phenylsulfonylamino)ethyl]phenoxyacetic acid (BM 13,505) [Stegmeier et al, Proc. EDTA ERA 22:1012 (1985) U.S. Pat. No. 4,258,058];
N,N'-[7-(3-chlorobenzene aminosulfonyl)-1,2,3,4-tetrahydroisoquinolyl]disulfonamide (SKF 88046) [Weichman et al, Prostaglandins Leukotrienes Med 15:167 (1984);
SQ29548 [1S-[1.alpha.,2.beta.(5Z), 3.beta.,4.alpha.]]-7-[3-[[2-phenylamino)carbonyl]hydrazino]methyl]-7-oxabi cyclo[2.2.1]hept-2-yl]-5-heptenoic acid [Ogletree et al, J. Pharmacol. Exp. Ther. 234:435 (1985)];
AH23848 [Brittain et al, Circ. 72:1208 (1985)];
13APA [LeBreton et al, Proc. Natl. Acad. Sci. U.S.A. 76:4097 (1979)]; and
ON03708 Kutsura et al, Adv. Pros. Thromb. LK. Res. 11:351 (1983)].
Plasminogen activators disclosed in European 0265129Al include streptokinase (SK), urokinase (UK) and tissue plasminogen activator (tPA), as well as related fibrinolytics such as acylated plasminogen streptokinase activator complex, prourokinase, single chain urokinase (SCUPA), antibody-bound plasminogen activators and hybrid tPA-UK proteins and other so-called "third generation" thrombolytics.
Lefer, A. M. et al, "Potentiation of Myocardial Salvage by Tissue Type Plasminogen Activator in Combination with a Thromboxane Synthetase Inhibitor in Ischemic Cat Myocardium" Circ. Res. Vol. 63, No. 3, Sept. 1988, discloses the use of a combination of tissue type plasminogen activator and a thromboxane synthetase inhibitor (CGS-13080) to preserve myocardial integrity in animals subjected to acute myocardial ischemia.
U.S. Patent No. 4,661,469 to Sarnoff discloses that the absorption rate of t-PA in the blood is enhanced by utilizing with the t-PA dosage, a dosage of an absorption enhancing agent for t-PA, preferably hydroxylamine hydrochloride, as well as ammonia, ammonium salts, urea and derivatives thereof, and alkyl and aryl hydroxylamines. In Column 12, starting at line 39, it is indicated that
"It has also been found that to prevent reocclusions or platelet aggregation it is desirable to either:
1. inhibit synthesis of thromboxane A (thromboxane A.sub.2) with a thromboxane synthetase inhibitor, e.g. an imidazole such as 4-(2-[1H-imidazol-1-yl)ethoxy)benzoic acid, hydrochloride (dazoxiben);
2. introduce an antagonist for the receptor of the thromboxane A (thromboxane A.sub.2) such as [1.alpha.,2.beta.(5Z),3.beta.(1E),4.alpha.]-7-[3-(3-cyclohexyl-3-hydroxy-1 -7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid) (SQ27,427);
3. introduce another inhibitor of platelet aggregation, e.g aspirin, indomethacin, naproxin, and sulfinpyrazone."